Over the past quarter-century, techniques have been developed and refined for the organic synthesis of diverse molecules of biological relevance. In particular, sophisticated methods have been developed for peptide synthesis. These methods have made possible the chemical synthesis of naturally-occurring peptides of interest for research or therapeutic purposes. In addition, many peptide structures have been synthesized for which there is no known naturally-occurring counterpart. It is now possible to synthetically prepare branched or cyclic peptides, or peptides in which one or more amino acid residues are glycosylated, sulfated, phosphorylated or otherwise derivatized. The state of the peptide synthetic art is reviewed in Barany et al. (1987), 30INT. J. PEPT. PROT. RES. 705-739 and Fields et al. (1992), in SYNTHETIC PEPTIDES: A USER'S GUIDE, 77-183 (Grant, ed.).
For many years, peptide structures were synthesized manually, a laborious process which required significant levels of expertise and was vulnerable to introduced error. Recently, instruments have been developed for automated peptide synthesis, an advance which significantly expands the range and variety of peptide structures that can be made. Automation allows for the preparation of peptides on a larger scale than could previously be attempted. Automated peptide synthesis instrumentation and software have greatly expanded the accessibility of peptide synthesis to academic and industrial investigators in fields beyond organic synthesis and protein chemistry. Synthesized peptide structures are now used as tools in such diverse fields as nutrition, microbiology, immunology, physiology and medicine.
With the increasing sophistication and variety of peptide synthetic techniques that have been reported, however, there has been an increasing awareness of the many limitations and undesired side-reactions that may be provoked. Many of these are idiosyncratic to a particular synthetic reagent or type of amino acid derivative, and effectively limit the range of conditions and combinations in which such reagents can be used. Many reagent- and amino acid-specific undesired side-reactions are also reviewed in Barany et al. (1987), Id. at 727-730.
Many additional and unexpected limitations and undesired side-reactions have been encountered by those adapting manual peptide synthetic techniques for use on instruments for automated peptide synthesis. Efforts to adapt existing methods of peptide synthesis for use in an automated setting, and to develop new methods uniquely suited for automated instrumentation, are presently ongoing. Many desired techniques for peptide synthesis have thus far proven incompatible with automated instrumentation.
For example, synthetic reactions involving allyl-protected amino acid derivatives have proven poorly adaptable to an automated setting. Removal of the allyl group has proven particularly difficult during automated synthesis, due to the nature and physical characteristics of the catalyst relied upon for allyl deprotection.